Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype
Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype
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DOI：
10.1161/atvbaha.115.305438
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发表时间：
2015-05-01
影响因子：
8.7
通讯作者：
Werstuck, Geoff H.
中科院分区：
文献类型：
--
作者：
McAlpine, Cameron S.;Huang, Aric;Werstuck, Geoff H.
β-糖原合酶激酶（GSK）-3 α/β与糖尿病、癌症、阿尔茨海默病和动脉粥样硬化的发病机制有关。GSK 3 α和β在动脉粥样硬化中的组织特异性和同源特异性功能尚不清楚。本研究探讨了肝细胞或骨髓细胞中GSK 3 α或GSK 3 β缺失对低密度脂蛋白受体（LDLR）（-/-）小鼠动脉粥样硬化的影响。方法和结果-我们消融了低密度脂蛋白受体（LDLR）-/-小鼠肝细胞或骨髓细胞中GSK 3 α或GSK 3 β的表达，并给小鼠喂高脂饮食10周。肝细胞或骨髓细胞中的GSK 3 α或GSK 3 β缺乏不影响代谢参数，包括血脂水平。肝脏中GSK 3 α或GSK 3 β的缺失并不影响动脉粥样硬化或肝脏脂质含量的发展。GSK 3 α髓样缺失，而非GSK 3 β髓样缺失，可减少动脉粥样硬化病变体积和病变复杂性。骨髓细胞中缺乏GSK 3 α的小鼠具有较低的炎症和更多的抗炎血浆细胞因子谱。髓系GSK 3 α缺陷小鼠动脉粥样硬化病变内的巨噬细胞，而不是GSK 3 β缺陷小鼠，显示与M1巨噬细胞极化相关的标志物表达减少，M2标志物表达增强。最后，分离骨髓源性巨噬细胞，并在体外分化为经典的M1巨噬细胞或替代的M2巨噬细胞。GSK 3 α缺失，而不是GSK 3 β缺失，减弱了与M1极化相关的基因的表达，同时通过调节STAT 3和STAT 6 activation.Conclusions-Our研究结果表明，髓样GSK 3 α缺失通过促进M2巨噬细胞表型减弱了动脉粥样硬化的进展。
Objective-Glycogen synthase kinase (GSK)-3 alpha/beta has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue-and homolog-specific functions of GSK3 alpha and beta in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3 alpha or GSK3 beta on atherosclerosis in low-density lipoprotein receptor (LDLR)(-/-) mice.Approach and Results-We ablated GSK3 alpha or GSK3 beta expression in hepatic or myeloid cells of LDLR-/- mice, and mice were fed a high-fat diet for 10 weeks. GSK3 alpha or GSK3 beta deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3 alpha or GSK3 beta did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3 alpha, but not of GSK3 beta, reduced atherosclerotic lesion volume and lesion complexity. Mice lacking GSK3 alpha in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3 alpha-deficient mice, but not of GSK3 beta-deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow-derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3 alpha deletion, but not GSK3 beta deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization by modulating STAT3 and STAT6 activation.Conclusions-Our findings suggest that deletion of myeloid GSK3 alpha attenuates the progression of atherosclerosis by promoting an M2 macrophage phenotype.